Open access Protocol Stroke Vasc Neurol: first published as 10.1136/svn-2020-000791 on 5 May 2021. Downloaded from Clopidogrel with aspirin in High-­risk patients with Acute Non-disabling­ Cerebrovascular Events II (CHANCE-2): rationale and design of a multicentre randomised trial

Yongjun Wang,1,2 Claiborne Johnston ‍ ‍ ,3 Philip M Bath,4 Xia Meng,1,2 Jing Jing,1,2 Xuewei Xie ‍ ‍ ,1,2 Anxin Wang ‍ ‍ ,1,2 Yuesong Pan ‍ ‍ ,1,2 Anding Xu ‍ ‍ ,5 Qiang Dong,6 Yilong Wang,1,2 Xingquan Zhao,1,2 Zixiao Li,1,2 Hao Li ‍ ‍ ,1,2 For the CHANCE-2 Investigators

To cite: Wang Y, Johnston C, ABSTRACT High-­risk patients with Acute Non-­disabling Bath PM, et al. Clopidogrel Background In patients with a minor ischaemic stroke Cerebrovascular Events (CHANCE) trial and with aspirin in High-risk­ or transient ischaemic attack (TIA), separate trials have patients with Acute Non-­ the Platelet-­Oriented Inhibition in New TIA shown that dual antiplatelet therapy with clopidogrel plus disabling Cerebrovascular and Minor Ischaemic Stroke (POINT) trial, a Events II (CHANCE-2): rationale aspirin (clopidogrel–aspirin) or ticagrelor plus aspirin lower risk of stroke recurrence was observed and design of a multicentre (ticagrelor–aspirin) are more effective than aspirin alone with a combination of clopidogrel and aspirin in stroke secondary prevention. However, these two sets randomised trial. Stroke & (clopidogrel–aspirin) than with aspirin Vascular Neurology 2021;0. of combination have not been directly compared. Since 3 4 doi:10.1136/svn-2020-000791 clopidogrel was less effective in stroke patients who were alone. However, the choice of an optimal CYP2C19 loss-­of-­function (LOF) allele carriers, whether dual antiplatelet therapy regimen for patients ►► Additional online with strokes requires a tailored approach supplemental material is ticagrelor–aspirin is clinically superior to clopidogrel– published online only. To view, aspirin in this subgroup of patients with stroke is unclear. based on the characteristics of the patient. please visit the journal online Aim To describe the rationale and design considerations The genetic substudy of the CHANCE trial (http://dx.​ ​doi.org/​ ​10.1136/​ ​svn-​ of the Clopidogrel in High-­risk patients with Acute Non-­ showed that clopidogrel plus aspirin reduced 2020-000791).​ disabling Cerebrovascular Events (CHANCE-2) trial. the risk of stroke recurrence in non-­carriers Design CHANCE-2 is a randomised, double-­blind, double-­ http://svn.bmj.com/ Received 9 December 2020 of the cytochrome P450 2C19 (CYP2C19) dummy, placebo-­controlled, multicentre trial that compares Revised 15 March 2021 loss-of-­function­ (LOF) alleles compared Accepted 9 April 2021 two dual antiplatelet strategies for minor stroke or TIA with aspirin alone but not in carriers. There- patients who are CYP2C19 LOF allele carriers: ticagrelor fore, clopidogrel may not provide additional (180 mg loading dose on day 1 followed by 90 mg twice benefit in stroke prevention compared with daily on days 2–90) or clopidogrel (300 mg loading dose on 5 day 1 followed by 75 mg daily on days 2–90), plus open-­ aspirin alone for the carriers. More recently, on September 28, 2021 by guest. Protected copyright. label aspirin with a dose of 75–300 mg on day 1 followed the substudy of POINT failed to reproduce by 75 mg daily on day 2–21. All will be followed for 1 year. the above findings as seen in the CHANCE 6 Study outcomes The primary efficacy outcome is any trial, possibly from a limited statistical power. stroke (ischaemic or haemorrhagic) within 3 months and In addition, a meta-analysis­ of 15 studies that the primary safety outcome is any severe or moderate included 4762 patients with stroke or TIA bleeding event within 3 months. found that carriers of CYP2C19 LOF alleles Discussion The CHANCE-2 trial will evaluate whether were at higher risk of vascular events than ticagrelor–aspirin is superior to clopidogrel–aspirin for non-carriers­ when taking clopidogrel.7 minor stroke or TIA patients who are CYP2C19 LOF allele Ticagrelor is a reversible oral antago- carriers. © Author(s) (or their nist directly blocking the P2Y12-­adenosine Trial registration number NCT04078737. employer(s)) 2021. Re-­use diphosphate receptor that needs no catab- permitted under CC BY-­NC. No commercial re-­use. See rights olite activation, which in turn yields greater and permissions. Published by INTRODUCTION AND RATIONALE mean levels of platelet inhibition than clopi- BMJ. In patients with acute non-disabling­ cerebro- dogrel.8 9 From the Acute Stroke or Tran- For numbered affiliations see vascular events, including those with acute sient Ischaemic Attack Treated with Aspirin end of article. minor stroke or transient ischaemic attack or Ticagrelor and Patient Outcomes trial (TIA), the subsequent recurrent stroke and involving participants with acute ischaemic Correspondence to Dr Yongjun Wang; cardiovascular events are more than 6% in stroke or TIA, ticagrelor was not found to 1 2 yongjunwang@​ ​ncrcnd.org.​ ​cn the first year. As shown in Clopidogrel in be more effective than aspirin in reducing

Wang Y, et al. Stroke & Vascular Neurology 2021;0. doi:10.1136/svn-2020-000791 1 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000791 on 5 May 2021. Downloaded from the risk of 90-­day vascular events.5 However, among Genotyping the Asian patients, a tendency towards better efficacy In this study, a novel point-­of-­care genetic test platform was seen in a subgroup analysis.10 The Platelet Reac- will be used to identify carriers of CYP2C19 LOF alleles tivity in Acute Stroke or Transient Ischaemic Attack including poor metabolisers with at least two *2 or *3 trial showed that participants with ischaemic stroke or alleles (*2/*2, *2/*3, or *3/*3) or intermediate metab- TIA who were treated with ticagrelor plus aspirin (tica- olisers with one *2 or *3 allele (*1/*2 or *1/*3). The grelor–aspirin) had a lower proportion of high platelet CYP2C19 genotyping will be implemented by the GMEX reactivity than those who were treated with clopidogrel– Point-­of-­Care Genotyping system, including a portable aspirin, particularly in the those who were CYP2C19 LOF DNA analyser, genotyping reagents, and a buccal sample allele carriers.11 The Acute Stroke or Transient Isch- collection kit. The system uses non-invasive­ sampling aemic Attack Treated with Ticagrelor and Aspirin for by buccal swab and integrates automated steps of DNA Prevention of Stroke and Death trial showed that dual extraction, PCR-­based amplification, fluorescent signal antiplatelet therapy (ticagrelor–aspirin) was better than detection and genotype determination. The system inte- mono antiplatelet therapy (aspirin) for secondary stroke grates controls to monitor the performance of a run prevention in people with mild-­to-­moderate acute isch- and ensure ongoing quality from the GMEX system. aemic stroke or TIA, but the rate of haemorrhage was The analysis includes the single nucleotide polymor- also elevated.12 phisms CYP2C19*2 (681G>A, rs4244285), CYP2C19*3 While separate trials have shown similar treatment (636G>A, rs4986893), and CYP2C19*17 (−806C>T, effects, no direct comparison has been conducted in this rs12248560), which will be genotyped on screening. patient population. In some populations, more than 50% The average result turn-around-­ ­time for the method of 13 of them carry CYP2C19 LOF alleles so that the conver- GMEX is 85 min. sion to an active form of clopidogrel is reduced. We hence hypothesised that, compared with clopidogrel– Randomisation aspirin, ticagrelor–aspirin may favourably impact the Participants will be randomised (1:1) to receive either clinical outcomes in high-risk­ participants with acute non-­ ticagrelor–aspirin or clopidogrel–aspirin. A randomisa- disabling cerebrovascular events and were carriers of the tion sequence will be generated centrally using random-­ CYP2C19 LOF allele. Therefore, the CHANCE-2 trial was permuted fixed-size­ blocks methods from the Statistics designed to test such hypothesis. The intention of this trial and Data Centre at the China National Clinical Research is to evaluate the safety and efficacy of ticagrelor–aspirin Centre for Neurological Diseases. The randomisation versus clopidogrel–aspirin for minor stroke or high-­risk computer program makes the treatment assignment TIA patients who were CYP2C19 LOF allele carriers. This based on the current status of treatment group distribu- article describes the design of the CHANCE-2 trial and is tion within each clinical centre as well as overall balance

a summary of protocol. of treatment assignment. Following randomised alloca- http://svn.bmj.com/ tion, the study intervention will be administered to the patient as early as possible. METHODS Design and patients population Intervention CHANCE-2 is a randomised, double-blind,­ double-­ Eligible participants are randomly assigned to one of two dummy, placebo-controlled­ multicentre trial. Patients arms: on September 28, 2021 by guest. Protected copyright. with CYP2C19 LOF alleles are randomised with 1:1 to one of the two strategies (ticagrelor–aspirin or clopi- Ticagrelor–aspirin group dogrel–aspirin) within 24 hours of the onset of cere- A 180 mg loading dose of Ticagrelor on day 1, followed brovascular Events. All participants will be followed by 90 mg two times per day on days 2–90 plus a 75–300 for 3 months on study intervention, with another 9 mg loading dose of aspirin, followed by 75 mg daily for months of follow-­up on standard of care. The study 21 days; design of the CHANCE-2 is shown in figure 1. The trial will enrol subjects age ≥40 years with acute non-­ Clopidogrel–aspirin group disabling ischaemic stroke, with a National Institutes A 300 mg loading dose of clopidogrel on day 1, followed of Health Stroke Scale (NIHSS) score ≤3 or high-­risk by 75 two times per day on days 2–90 plus a 75–300 mg TIAs (ABCD2 score ≥4). Once randomised, they will be loading dose of aspirin followed by 75 mg daily for 21 treated with study drug within 24 hours of symptoms days. onset. Figure 2 lists the summary of inclusion and exclu- Patient will take the first dose of the study drug on the sion criteria. Prior to initiating the study, each clinical first visit. Then, for the next 12 weeks, the study drug site obtains institutional review board (IRB) approval should be taken twice daily, 12 hours apart. Once the study for the protocol, informed consent, and materials used period is over at the end of 12th week, the treating physi- to recruit subjects. Participants from 240 hospitals in cian will decide what antiplatelet drug to be continued. China will be enrolled in CHANCE-2. All participants will be followed for 1 year.

2 Wang Y, et al. Stroke & Vascular Neurology 2021;0. doi:10.1136/svn-2020-000791 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000791 on 5 May 2021. Downloaded from http://svn.bmj.com/ on September 28, 2021 by guest. Protected copyright.

Figure 1 CHANCE-2 study design. CHANCE-2, Clopidogrel in High-­risk patients with Acute Non-disabling­ Cerebrovascular Events; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischaemic attack；ASA，aspirin; ULN, upper limit of normal; ALT, alanine aminotransferase; AST，aspartate transaminase；AV, atrioventricular.

Wang Y, et al. Stroke & Vascular Neurology 2021;0. doi:10.1136/svn-2020-000791 3 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000791 on 5 May 2021. Downloaded from not lead to haemodynamic compromise requiring inter- vention. Other secondary safety outcomes include the following events within a 3-month­ and 1-year­ time frame: (1) Incidence of severe bleedings or moderate bleed- ings (GUSTO definition) at 1 year; (2) Bleeding events; (3) Mortality; (4) Adverse events (AEs)/serious adverse events (SAEs) reported by the investigators.

Data safety and monitoring board To ensure ethically conduct of the trial and patient safety, the data safety and monitoring board (DSMB) will meet per protocol and monitor the progress of the trial. Members of DSMB do not participate in the trial and Figure 2 Summary of inclusion and exclusion criteria. their responsibilities are defined by the trial Executive HR-­NICE, high-­risk patients with acute non-disabling­ Committee prior to the beginning of the trial. DSMB will cerebrovascular events (TIA or acute minor stroke); LOF, loss-­ provide their recommendations in written statement to of-­function. the Chairs of trial Steering Committee after each meeting.

Sample size Primary outcomes The sample size calculation is based on the rate of the The primary efficacy outcome is any stroke (ischaemic or primary outcome (3-­month risk of stroke) and estimated haemorrhagic) within 3 months. Definitions of stroke are effect size. We used the following assumptions: (1) Signif- provided in online supplemental table 1. icance level of 0.048 for a two-­sided test; (2) Statistical power of 90%; (3) 3-month­ rate of stroke event is 9.4% in Secondary outcomes control group based on the data from the CHANCE trial5; Secondary outcomes include the following events: (1) (4) Proportional risk reduction of 25% (Rate ratio=0.75); Any new stroke events within 30 days and 1 year; (2) New (5) of 5% over 3 months. We estimated that 6396 eligible clinical vascular events including stroke, TIA, myocardial patients (3198 for each treatment group) are required. infarction and vascular deaths within 3 months and 1 As 58.8% of patients are CYP2C19 LOF allele carriers,5 we year ; (3) New ischaemic stroke within 3 months and 1 need to screen about 10 878 patients in total. year; (4) Disabling stroke (Modified Rankin Scale score, mRS >1) at 3 months and 1 year; (5) Incidence and Interim analysis severity of recurrent stroke and TIA during follow-up­ to 3 The interim analysis will focus on patient recruitment,

months and 1 year. Severity is measured using a six-­level baseline comparability of treatment arms, sample sizes http://svn.bmj.com/ ordered categorical scale that incorporates the mRS: fatal with regard to event rates, loss to follow-up,­ adverse effects stroke/severe non-­fatal stroke (mRS 4 or 5)/moderate data and effect of treatment on the primary endpoints. We stroke (mRS 2 or 3)/mild stroke (mRS 0 or 1)/TIA/no plan one interim analysis when 60% of total patients have stroke-­TIA; (6) Neurological impairment at 3 months undergone randomisation and completed the follow-up.­ (NIHSS increased ≥4 from baseline); (7) Quality of Life The sample size is inflated to account for one interim (EuroQol-5dimension) scale. The influence on treatment analysis of the primary efficacy outcome with the use of on September 28, 2021 by guest. Protected copyright. effect of age, gender, body mass index, index event type an O’Brien-Fleming­ spending function, and a p<0.008 is (TIA vs minor stroke), time from index event to randomi- considered to be statistically significant during the interim sation, aetiology subtype, diabetes mellitus, hypertension, analysis. In the final analysis, a p<0.048 is considered to be type of LOF allele, previous ischaemic stroke or TIA, prior statistically significant in the current study. Trial investiga- antiplatelet therapy, prior statin therapy, prior smoking tors will be blinded to the interim outcome results. status and symptomatic intracranial and extracranial artery stenosis will be evaluated in subgroup analyses. Statistical analyses An intention-to-­ ­treat analysis will be used for all partici- Safety outcomes pants randomised to an intervention group. Participants The primary safety outcome is severe or moderate will be censored at their last follow-up­ assessment when bleeding event within 3 months. The bleeding event is experiencing a clinical event, at the end of study, or at defined by the criteria from the Global Utilisation of Strep- the time of withdrawal from the study. Statistically, the tokinase and Tissue Plasminogen Activator for Occluded cumulative risk of any ischaemic or haemorrhagic event Coronary Arteries (GUSTO) trial.14 Severe haemorrhage will be reported as a Kaplan-­Meier estimates during the is defined as fatal or intracranial haemorrhage or other 90-day­ follow-­up. Cox proportional hazards methods will haemorrhage causing haemodynamic compromise that be used for HR calculation at 95% CIs. The treatment requires blood or fluid replacement, inotropic support or effect will be assessed by the log-­rank test. This approach surgical intervention. Moderate haemorrhage is defined is to maximise the time-dependent­ information in the as bleeding that required transfusion of blood but does trial while still acknowledge the ease of interpretation of

4 Wang Y, et al. Stroke & Vascular Neurology 2021;0. doi:10.1136/svn-2020-000791 Open access Stroke Vasc Neurol: first published as 10.1136/svn-2020-000791 on 5 May 2021. Downloaded from risks. Accounting for a single interim analysis, a p value of 6Department of Neurology, Huashan Hospital, State Key Laboratory of Medical 0.048 will be considered to indicate statistical significance Neurobiology, Fudan University, Shanghai, China for the primary outcome. Detailed analysis plans will be Twitter Yilong Wang @yilong given in the statistical analysis plan before the database is locked and the blind is broken. Contributors YW, CJ, PMB, A-DX­ and QD contributed to the design of the study and contribute to its oversight. HL, XM, XX, JJ, AW and YP coordinated the study. YW and XX wrote the first draft of the manuscript, which was edited by all other authors. Study organisation Funding The Ministry of Science and Technology of the People’s Republic of The Trial Steering Committee provides oversight and stra- China (MOST), Beijing Municipal Science and Technology Commission and Chinese tegic input and will meet twice yearly. The Trial Manage- Stroke Association (CSA) fund CHANCE-2. This work was supported by grants ment Committee runs the trial on a day-to-­ ­day basis and from National Science and Technology Major Project (2017ZX09304018) and is based at the CHANCE-2 Trial Coordinating Centre of Beijing Municipal Science and Technology Commission (D171100003017002). Salubris contributes ticagrelor, clopidogrel and its placebo at no cost and with the China National Clinical Research Centre for Neuro- no restrictions. The principal investigator and executive committee will have full logical Diseases. Outcomes, SAEs, and brain imaging are access to the entire dataset at trial completion and are responsible for analysis and adjudicated by trained assessors masked to treatment publication in collaboration with the sponsor. assignment. Competing interests None declared. Patient consent for publication Not required. Ethics approval The CHANCE-2 trial was approved by ethics committee at Beijing DISCUSSION Tiantan Hospital (IRB approval number: KY2019-035-02) and all participating centres CHANCE-2 will address a major issue in secondary Provenance and peer review Not commissioned; externally peer reviewed. prevention in those TIA or minor stroke patients who are Data availability statement Data sharing not applicable as no datasets generated CYP2C19 LOF allele carriers. Furthermore, the safety and and/or analysed for this article. efficacy of ticagrelor–aspirin or clopidogrel–aspirin will Open access This is an open access article distributed in accordance with the be assessed. Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially­ , Two recent RCTs revealed that the short term clopi- and license their derivative works on different terms, provided the original work is dogrel–aspirin therapy is beneficial after acute minor properly cited, appropriate credit is given, any changes made indicated, and the use stroke or TIA.3 4 However, several studies have showed is non-­commercial. See: http://​creativecommons.org/​ ​licenses/by-​ ​nc/4.​ ​0/. the higher risk of poor clinical outcomes in CYP2C19 15–18 ORCID iDs LOF allele carriers who receiving clopidogrel. A Claiborne Johnston http://orcid.​ ​org/0000-​ ​0002-2912-​ ​0714 genetic substudy of the Secondary Prevention of Small Xuewei Xie http://orcid.​ ​org/0000-​ ​0001-8154-​ ​1957 Subcortical Strokes trial reported that patients with one Anxin Wang http://orcid.​ ​org/0000-​ ​0003-4351-​ ​2877 CYP2C19 LoF allele carriers had higher odds of stroke Yuesong Pan http://orcid.​ ​org/0000-​ ​0003-3082-​ ​6789 19 Anding Xu http://orcid.​ ​org/0000-​ ​0003-3154-​ ​0985 recurrence compared with non-­carriers. A preplanned Hao Li http://orcid.​ ​org/0000-​ ​0002-8591-​ ​4105 substudy of the CHANCE trial found that CYP2C19 LoF carriers had 1.5 times the risk of recurrent stroke as non-­ http://svn.bmj.com/ carriers at 90 days.5 To date, there is no evidence from randomised trials for a direct comparison of treatment REFERENCES effect between ticagrelor and clopidogrel with aspirin 1 Amarenco P, Lavallée PC, Labreuche J, et al. One-year­ risk of added on for secondary stroke prevention. 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